Process For The Manufacture Of A Pharmaceutical Product

ABSTRACT

A process for the preparation of a pharmaceutical composition comprising a homogeneous or substantially homogeneous mixture of citric acid, magnesium oxide, potassium bicarbonate and sodium picosulphate and, optionally, saccharin sodium and/or orange flavor; products, intermediate products, and uses thereof.

The present invention relates to an improved process for the manufactureof a pharmaceutical product, and products and intermediate productsresulting therefrom.

BACKGROUND OF THE INVENTION

A pharmaceutical product used for clearance of the bowel prior to X-rayexamination, endoscopy or surgery, is presently sold under the trademark name of PICOLAX™. The pharmaceutical product is a white powderwhich is made up as a solution (in water) for administration. Theproperties required are that it is a strong laxative that is easilypalatable. The pharmaceutical product includes sodium picosulphate (PS),a stimulant laxative; and anhydrous citric acid (CA) and magnesium oxide(MgO, light), which together in solution form magnesium citrate, anosmotic laxative with a powerful cathartic effect.

The dosage form for oral delivery is in the form of granules. Herein theterm granule(s) includes loose particles (such as particles which mightcollectively be termed a powder, including loose particles in the formof a powder which is known in the art as “powder for oraladministration”). The product is a physical mixture of six rawmaterials; these being citric acid (e.g. citric acid anhydrous or citricacid monohydrate), magnesium oxide (e.g. magnesium oxide light),potassium bicarbonate (KHCO₃), sodium picosulphate (NaPIC), sodiumsaccharin, and orange flavour. Magnesium oxide “light” means, herein,magnesium oxide having an apparent volume such that 15 g occupiesbetween 75 to 180 ml, e.g 15 g occupies a volume of 150 ml.

The known process for making PICOLAX™ may include the following steps.Granules of magnesium oxide and citric acid are produced by mixing thetwo reagents together—this is known as the “primary mix”. In anotherstage, potassium bicarbonate, sodium picosulphate and water are mixed orblended to produce a wet “pre-mix”, which is then dried. In a furtherstage, the flavour ingredients, orange flavour and sodium saccharin, areblended with the pre-mix and primary mix. The known process has severalassociated problems.

Firstly, the mixing processes may result in inhomogeneity problems inthe final and intermediate products. In one aspect, the terms“inhomogeneity” and “lack of homogeneity” as used in this applicationrefer to the lack of uniformity of content of the activesubstance—sodium picosulphate—in e.g. the final product. It also refersto the lack of homogeneity in the physical and morphological properties,such as the particle size (diameter) or particle size range ordistribution, of the intermediate products and/or the final productgranules. Intermediate product granules are, for example the primary mixgranules or the pre-mix granules.

Homogeneity has been suspected to be at least one of the criticalfactors assuring the quality and performance of the final product, andit is believed that product homogeneity (and inhomogeneity) relates tothe mixing processes used. Thus, in the first stage of the knownprocess, disparities may occur in the granule size and distribution(i.e. inhomogeneity may arise) because of the low binding properties oragglomeration properties between citric acid and magnesium oxideparticles (caused by e.g the difference in densities of the twomaterials). Further, magnesium oxide is left on the mixer bowl, bladesetc. (rather than being mixed with the citric acid). Thus, in the knownprocess, extra magnesium oxide (“overage”) is included in the rawmaterials to compensate for losses during the blending process. Theoverage is typically over 10%. This leads to economic losses over longerperiods and where larger quantities are produced. Additionally, longerprocessing times are entailed, and unhealthy amounts of dust may beproduced during mixing.

In the premix stage, lack of homogeneity of the resulting granules mayarise due to dissolution of some potassium bicarbonate in thegranulation medium, water, and because of physical degradation(smashing) of the particles during mixing. This may have a detrimentaleffect on the final product. Further, long processing times, andmultiple steps, are required to complete this stage of the process(which takes typically 15 to 24 hours).

Thus, there is a need for an improved manufacturing process.

SUMMARY OF THE INVENTION

The present applicants have developed a process which may alleviate someor all of the problems of the prior art process, and e.g. provide animproved product and/or a marked reduction in processing time.

There is provided therefore, according to an aspect of the presentinvention, a process for the preparation of a pharmaceutical compositioncomprising a homogeneous or substantially homogeneous mixture of citricacid, magnesium oxide, potassium bicarbonate and sodium picosuiphateand, optionally, saccharin sodium and/or orange flavour, comprising:

a) dry mixing citric acid and magnesium oxide;

b) applying (e.g. spraying) a solution of sodium picosulphate onto thepotassium bicarbonate; and drying said sodium picosuiphate and potassiumbicarbonate; and

c) mixing at least a part of the product of step a) with at least a partof the product of step b) and, optionally, saccharin sodium and/ororange flavour.

In one example, the process includes a further step d) of mixing theproduct of step c) with further amount of a mixture formed by dry mixingcitric acid and magnesium oxide [e.g. some or all of the remainingproduct of the process defined in step a)]; and/or a product formed byapplying (e.g. spraying) a solution of sodium picosulphate on topotassium bicarbonate and drying the sodium picosuiphate and potassiumbicarbonate [e.g. some or all of the remaining product of the processdefined in step b)].

Thus, in one aspect there is provided a process for the preparation of apharmaceutical composition, comprising a homogeneous or substantiallyhomogeneous mixture of citric acid, magnesium oxide, potassiumbicarbonate and sodium picosuiphate and, optionally, saccharin sodiumand/or orange flavour, comprising:

a) dry mixing citric acid and magnesium oxide;

b) applying (e.g. spraying) a solution of sodium picosulphate onto thepotassium bicarbonate; and drying said sodium picosulphate and potassiumbicarbonate;

c) mixing at least a part of the product of step a) with at least a partof the product of step b) and, optionally, saccharin sodium and/ororange flavour; and

d) mixing the product of step c) with some or all of the remainingproduct of the process defined in step a); and/or some or all of theremaining product of the process defined in step b).

The product homogeneous or substantially homogeneous mixture of citricacid, magnesium oxide, potassium bicarbonate and sodium picosulphateand, optionally, saccharin sodium and/or orange flavour may be in theform of granules. The granule(s) may have a particle size (diameter)range or distribution of between about 100 and about 900 μm, e.g.between about 150 and 875 μm, e.g. between about 250 and about 850 μm.The pharmaceutical composition may be in the form of granules of e.g. aparticle size (diameter) range or distribution of between about 100 andabout 900 μm, e.g. between about 150 and 875 μm, e.g. between about 250and about 850 μm.

It will be appreciated that herein the term diameter is not intended tomean that any of the particles and granules disclosed are spherical. Asis clearly shown in the attached drawings the granules may be, forexample, roughly spherical, in the form of elongated spheres(ellipsoidal) etc. Herein the term size (diameter) is intended to meanthe shortest distance in a straight line passing from one side to theother through the centre point of the granule (e.g. sphere, roughsphere, elongated sphere, ellipsoid).

According to the present invention in a further aspect, there isprovided a granule or granules or a pharmaceutical composition,comprising a homogeneous or substantially homogeneous mixture of citricacid, magnesium oxide, potassium bicarbonate and sodium picosulphate,and, optionally, saccharin sodium, and orange flavour. Thepharmaceutical composition of the present invention may be used forclearance of the bowel prior to X-ray examination, endoscopy or surgery.The granule(s) may have a particle size (diameter) range or distributionof between about 100 and about 900 μm, e.g. between about 150 and 875μm, e.g. between about 250 and about 850 μm.

Said granule(s) or pharmaceutical composition may be dispensed assachets.

The uniformity of content of the active substance, sodium picosulphate,in the final product granule(s) or pharmaceutical composition may have amean value of about 0.0559% and 0.068% by weight (9.0-11.0 mg/dose,based on a dose of 16.1 g PICOLAX™).

According to the present invention in a further aspect, there isprovided a pharmaceutical preparation or pharmacetical compositioncomprising product granules of a homogeneous or substantiallyhomogeneous mixture of a first composition comprising (first) granulesof citric acid and magnesium oxide as described herein (e.g. comprisinggranules including citric acid and magnesium oxide, the granulescomprising a layer of magnesium oxide coated on a core of citric acid);and a second composition comprising (second) granules of potassiumbicarbonate and sodium picosulphate as described herein (e.g. comprisinggranules including sodium picosulphate and potassium bicarbonate, thegranules comprising a layer of sodium picosulphate coated on a core ofpotassium bicarbonate); and, optionally, saccharin sodium and/or orangeflavour. The product granule(s) may have a particle size (diameter)range between about 100 and about 900 μm. The product granule(s) mayhave a uniformity of content of sodium picosulphate of mean valuebetween about 0.0559% and 0.068% by weight.

The process of the invention may include a separation (e.g. processinge.g. sieving) step or steps e.g. to obtain potassium bicarbonate ofappropriate size and/or size distribution—e.g. a particle size(diameter) range of, for example, between about 100 and about 900 μm,e.g. between about 150 and 875 μm, e.g. between about 250 and about 850μm—prior to applying (e.g. spraying). The process of the invention mayinclude a separation (e.g. processing e.g. sieving) step or steps e.g.to obtain citric acid of appropriate size and/or size distribution—e.g.a particle size (diameter) range of, for example, between about 100 andabout 900 μm, e.g. between about 150 and 875 μm, e.g. between about 250and about 850 μm—prior to mixing with magnesium oxide.

The present invention also provides a process for the preparation of apharmaceutical composition comprising a homogeneous or substantiallyhomogeneous mixture of citric acid, magnesium oxide, potassiumbicarbonate and sodium picosulphate and, optionally, saccharin sodiumand/or orange flavour (and/or a process for the preparation of acomposition comprising citric acid and magnesium oxide) comprising astep of dry mixing citric acid and magnesium oxide (e.g. magnesium oxidelight), using a means for forming a homogeneous mixture of compoundswith markedly different densities (such as a multi-dimension blender orthree-dimensional blender). The means may mix using a three-dimensionalmotion (e.g. that known as the Paul Schatz principle). The means may mixusing a three-dimensional motion which combines a figure-of-eightmovement with rotation, causing the substances within the mixer to movein a rhythmic, pulsating motion. The means may enhance the agglomerationprocess between citric acid and magnesium oxide. The means (e.g.multi-dimension blender or three-dimensional blender) may be closedduring mixing, which may prevent dust or contamination. The means (e.g.multi-dimension blender or three-dimensional blender) may mix by anaction whereby the mixing vessel is agitated or moved (e.g. spun) with athree dimensional motion, rather than by the use of a blade or paddlewithin the vessel (as in a conventional, planetary, mixer). The threedimensional motion may reduce particle damage (and inconsistent productsize) associated with conventional mixing techniques—e.g. caused byfrictional forces between the blade or paddle and mixing vessel side.

The citric acid may be loaded e.g. in a single batch into the means forforming a homogeneous or substantially homogeneous mixture of compoundswith markedly different densities (such as a multi-dimension blender orthree-dimensional blender), prior to addition of magnesium oxide. Themagnesium oxide may be added in e.g. two to six, e.g. four, batches,with mixing between addition of each batch. The addition of MgO in smallbatches to the full amount of citric acid, and the mixing in betweeneach addition of a batch of MgO, may enhance the agglomeration processbetween citric acid and magnesium oxide, and/or the homogeneity of theproduct mixture, and/or reduce the loss of MgO.

The process may include a separation (e.g. processing e.g. sieving) stepor steps e.g. to obtain citric acid of appropriate size and/or sizedistributiuon—e.g. a particle size (diameter) range of, for example,between about 100 and about 900 μm, e.g. between about 150 and 875 μm,e.g. between about 250 and about 850 μm—prior to mixing with magnesiumoxide. The process optionally includes one or more separation (e.g.sieving) steps e.g. to obtain product composition/granules ofappropriate size (diameter) and/or size distribution.

The (product) composition/granules may have a particle size (diameter)and/or particle size (diameter) distribution which is compatible withthe particle size or particle size distribution of the pre-mix or withthe product of a step of applying (e.g. spraying) sodium picosulphate onpotassium bicarbonate and drying.

According to a further aspect of the invention, granules (e.g. granuleswhich are agglomerated particles) of citric acid and magnesium oxide areprovided, having a particle size distribution range of between about 100and about 900 μm, e.g. between about 150 and 875 μm, e.g. between about250 and about 850 μm. The granules may have a particle size (diameter)distribution wherein more than 85%, for example more than 90%, forexample more than 92% of the particles have a particle size (diameter)between about 100 and about 900 μm, e.g. between about 150 and 875 μm,e.g. between about 250 and about 850 μm. The granules may have aparticle size (diameter) distribution wherein less than 5%, for exampleless than 2%, for example less than 1% of the particles have a particlesize (diameter) greater than about 850 μm; and/or wherein less than 5%,for example less than 2%, for example less than 1% of the particles havea particle size (diameter) less than about 250 μm. The granules may havea particle size (diameter) distribution wherein less than 5%, forexample less than 2%, for example less than 1% of the particles have aparticle size (diameter) greater than about 875 μm; and/or wherein lessthan 5%, for example less than 2%, for example less than 1% of theparticles have a particle size (diameter) less than about 150 μm. Thegranules may have a particle size (diameter) distribution wherein lessthan 5%, for example less than 2%, for example less than 1% of theparticles have a particle size (diameter) greater than about 900 μm;and/or wherein less than 5%, for example less than 2%, for example lessthan 1% of the particles have a particle size (diameter) less than about100 μm. The granules may have a particle size (diameter) range of, forexample, between about 100 and about 900 μm, e.g. between about 150 and875 μm, e.g. between about 250 and about 850 μm. The granules may havesize or size distribution which is compatible with mixing with theproduct of a step of applying (e.g. spraying) a solution of sodiumpicosulphate on to potassium bicarbonate; and drying the sodiumpicosulphate and potassium bicarbonate (e.g. step b). The granules mayinclude a layer of magnesium oxide coated on the citric acid.

According to a further aspect of the invention, there is provided acomposition comprising granules including citric acid and magnesiumoxide, the granules comprising a layer of magnesium oxide coated on acore of citric acid. The thickness of the layer of magnesium oxide maybe between 2 and 15 μm, for example between 5 and 10 μm. The granulesmay be between 450 and 800 μm broad (e.g. 500 to 700 μm broad) at theirbroadest point [i.e. at the longest distance in a straight line passingfrom one side of the granule to the other through the centre point ofthe granule (e.g. sphere, rough sphere etc.).

In a further aspect, the present invention provides a process for thepreparation of a pharmaceutical composition comprising a homogeneous orsubstantially homogeneous mixture of citric acid, magnesium oxide,potassium bicarbonate and sodium picosulphate and, optionally, saccharinsodium and/or orange flavour, (and/or a process for the preparation of acomposition comprising potassium bicarbonate and sodium picosulphate,)comprising a step of applying (e.g. spraying) a solution of sodiumpicosulphate on to the potassium bicarbonate; and drying the sodiumpicosulphate and potassium bicarbonate.

The potassium bicarbonate may have a particle size (diameter) range of,for example, between about 100 and about 900 μm, e.g. between about 150and 875 μm, e.g. between about 250 and about 850 μm. The process mayinclude a separation (e.g. sieving) step or steps e.g. to obtainpotassium bicarbonate of appropriate size and/or size distribution—e.g.a particle size (diameter) range of, for example, between about 100 andabout 900 μm, e.g. between about 150 and 875 μm, e.g. between about 250and about 850 μm.

The sodium picosulphate may be in aqueous solution. The ratio by weightof sodium picosulphate:water in the solution may be between 1:1 and 1:3,for example between 1:1.3 and 1:2.5, for example between about 1:1.5 and1:2. The sodium picosulphate solution—e.g. aqueous solution—may beapplied (e.g. sprayed) at a rate of 1 to 20 ml/min, preferably 10 to 12ml/min.

In one example the sodium picosulphate is in aqueous solution. Thesolution—e.g. aqueous solution—may be applied (e.g. sprayed) onto thesurface of e.g. granules or particles of potassium bicarbonate. Thesolution—e.g. aqueous solution—may be applied (e.g. sprayed) as e.g.micro-liquid drops.

The potassium bicarbonate may be preheated (e.g. prior to applying (e.g.spraying) the solution of sodium picosulphate on to the potassiumbicarbonate) e.g. to a temperature of between 30° to 100° C., e.g. 30°C. to 70° C., e.g. 30° C. to 50° C. The sodium picosulphate andpotassium bicarbonate may be dried at e.g. a temperature of between 30°to 100° C., e.g. 30° C. to 70° C., e.g. 30° C. to 50° C., for example45° C. The drying may be by using [e.g. applying e.g. blowing] warm orhot air (e.g. at a temperature of between 30° to 100° C., e.g. 30° C. to70° C., e.g. 30° C. to 50° C.). The drying may be during applying (e.g.spraying), and/or immediately or substantially immediately afterapplying (e.g. spraying). There may be one or more (e.g. 2, 3, 4 ormore) applications (by e.g. spraying) of sodium picosulphate solution,the sodium picosulphate and potassium bicarbonate being dried during orimmediately or substantially immediately after each (spray) application.

The applying (e.g. spraying) and drying may be performed e.g. in atumble coating machine, or other coating machine (e.g. fluid bed coatingmachine) known to the skilled man.

The applying (e.g. spraying) and drying of sodium picosulphate andpotassium bicarbonate may thus be finished in one step using the samecoating machine instead of requiring two or more separate (mixing,drying) steps, and/or two or more separate machines.

The process may be auto-controlled. Thus, manual operations may beavoided, again allowing a reduction in the total process time.

The process may include a separation (e.g. sieving) step or steps toobtain product of appropriate size and/or size distribution—e.g. aparticle size (diameter) range of, for example, between about 100 andabout 900 μm, e.g. between about 150 and 875 μm, e.g. between about 250and about 850 μm.

The (product) composition comprising potassium bicarbonate and sodiumpicosulphate may have a particle size (diameter) and/or particle size(diameter) distribution which is compatible with the particle size orparticle size distribution of the primary mix or product of the step ofdry mixing citric acid and magnesium oxide. The (product) compositioncomprising potassium bicarbonate and sodium picosulphate may have aparticle size (diameter) distribution wherein more than 85%, for examplemore than 90%, for example more than 92% of the particles have aparticle size (diameter) between about 100 and about 900 μm, e.g.between about 150 and 875 μm, e.g. between about 250 and about 850 μm.The (product) composition comprising potassium bicarbonate and sodiumpicosulphate may have a particle size (diameter) distribution whereinless than 5%, for example less than 2%, for example less than 1% of theparticles have a particle size (diameter) greater than about 850 μm;and/or wherein less than 5%, for example less than 2%, for example lessthan 1% of the particles have a particle size (diameter) less than about250 μm. The (product) composition comprising potassium bicarbonate andsodium picosulphate may have a particle size (diameter) distributionwherein less than 5%, for example less than 2%, for example less than 1%of the particles have a particle size (diameter) greater than about 875μm; and/or wherein less than 5%, for example less than 2%, for exampleless than 1% of the particles have a particle size (diameter) less thanabout 150 μm. The (product) composition comprising potassium bicarbonateand sodium picosulphate may have a particle size (diameter) distributionwherein less than 5%, for example less than 2%, for example less than 1%of the particles have a particle size (diameter) greater than about 900μm; and/or wherein less than 5%, for example less than 2%, for exampleless than 1% of the particles have a particle size (diameter) less thanabout 100 μm. The (product) composition comprising potassium bicarbonateand sodium picosulphate may have a particle size (diameter) range ordistribution of, for example, between about 100 and about 900 μm, e.g.between about 150 and 875 μm, e.g. between about 250 and about 850 μm.

The product or composition formed by applying (e.g. spraying) a solutionof sodium picosuiphate on to potassium bicarbonate and drying may be inthe form of granules or particles, possessing improved homogeneity.

According to the present invention in a further aspect there is provideda composition comprising granules including sodium picosulphate andpotassium bicarbonate, the granules comprising a layer of sodiumpicosulphate coated on a core of potassium bicarbonate. The granules maybe e.g. substantially ellipsoidal [e.g. in the shape of an elongatedsphere (see e.g. FIG. 2)]. The granules may be substantially ellipsoidalin shape with the shortest distance in a straight line passing from oneside of the granule to the other through the centre point of the granulebeing between 100 and 500 μm (e.g. 200 to 400 μm); and/or with thelongest distance in a straight line passing from one side (end) of thegranule to the other through the centre point of the granule beingbetween 500 and 900 μm (e.g. 550 to 750 μm).

According to another aspect of the invention, pre-mix granules of sodiumpicosuiphate and potassium bicarbonate, having a particle size(diameter) range or distribution of between about 100 and about 900 μm,e.g. between about 150 and 875 μm, e.g. between about 250 and about 850μm, are provided.

According to another aspect of the invention there is provided a granuleor granules comprising a layer of sodium picosuiphate coated onpotassium bicarbonate. The granules may have a particle size (diameter)distribution wherein more than 85%, for example more than 90%, forexample more than 92% of the particles have a particle size (diameter)between about 100 and about 900 μm, e.g. between about 150 and 875 μm,e.g. between about 250 and about 850 μm. The granules may have aparticle size (diameter) distribution wherein less than 5%, for exampleless than 2%, for example less than 1% of the particles have a particlesize (diameter) greater than about 850 μm; and/or wherein less than 5%,for example less than 2%, for example less than 1% of the particles havea particle size (diameter) less than about 250 μm. The granules may havea particle size (diameter) distribution wherein less than 5%, forexample less than 2%, for example less than 1% of the particles have aparticle size (diameter) greater than about 875 μm; and/or wherein lessthan 5%, for example less than 2%, for example less than 1% of theparticles have a particle size (diameter) less than about 150 μm. Thegranules may have a particle size (diameter) distribution wherein lessthan 5%, for example less than 2%, for example less than 1% of theparticles have a particle size (diameter) greater than about 900 μm;and/or wherein less than 5%, for example less than 2%, for example lessthan 1% of the particles have a particle size (diameter) less than about100 μm. The granules may have a particle size (diameter) range of, forexample, between about 100 and about 900 μm, e.g. between about 150 and875 μm, e.g. between about 250 and about 850 μm.

The pre-mix granules produced by methods of the present invention maypossess a content of uniformity of sodium picosulphate (mg dose) whichcontributes to the homogeneity of final product. The present inventionmay provide, an intermediate composition or pre-mix, comprisingpotassium bicarbonate and sodium picosulphate, in the form of granules,which have a specified content of uniformity of sodium picosulphate (mgdose) which is consistent with that of the final product granule(s) orpharmacutical composition (see above) and a particle size (diameter)range of between about 100 and about 900 μm, e.g. between about 150 and875 μm, e.g. between about 250 and about 850 μm.

It will be appreciated that herein process steps may be referred to asstep a), b), c) etc. for clarity only; there is no express or impliedrequirement regarding ordering of steps. Thus, for example, the step a)process may be completed before, after, or substantially simultaneouslywith step b).

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be illustrated with reference to thefollowing Examples and the attached drawings in which FIG. 1 shows SEMpicures and EDAX analysis results for Primary Mix granules of citricacid and magnesium oxide according to an embodiment of the invention;and FIG. 2 shows SEM picures and EDAX analysis results for Pre Mixgranules of sodium picosulphate and potassium bicarbonate according toan embodiment of the invention.

The product PICOLAX™ is a physical mixture of six raw materials; thesebeing citric acid (anhydrous), magnesium oxide, light, potassiumbicarbonate (KHCO₃), sodium picosulphate, saccharin sodium, and orangeflavour.

In the first stage of the known process for making PICOLAX™, asdiscussed above, the “primary mix” comprising magnesium oxide and citricacid, is first produced. Extra magnesium oxide (“overage”) is measuredin as part of the feed to compensate for losses during the blendingprocess. In the second stage, potassium bicarbonate, sodium picosulphateand water are mixed or blended to produce the “pre-mix”. The pre-mixgranulate is then dried. In the third stage, the flavour ingredients,orange flavour and sodium saccharin, are blended with the pre-mix andthe primary mix.

According to the present invention in some aspects, the process alsorequires several stages.

The Primary Mix

In the prior art process, disparities were found to occur in the granulesize and distribution, apparently due to the low binding properties oragglomeration properties between the citric acid and magnesium oxideparticles. The prior art equipment employed, which was typically atumble blender or planetary dry mixer, appeared to encourage separationof the two components, and loss of raw material in the form of fines,for example, of magnesium oxide. Using the known process, it isnecessary to compensate on a regular basis for losses by adding extramagnesium oxide (“overage”) in an amount of typically above 10%, whichleads to economic losses over longer periods and larger quantitiesproduced. Additionally, long processing times may be entailed, andunhealthy amounts of MgO dust may be produced during mixing. The priorart process may result in cleaning difficulties, and/or poor control ofproduct granule/particle size and distribution.

A stage or step of present invention involves dry mixing of citric acid(CA) and magnesium oxide, to produce the “primary-mix”. In contrast tothe prior process, a better-agglomerated mixture may be obtained bymixing the citric acid and magnesium oxide using e.g. a multi-dimensionblender or three-dimensional blender. The overage is significantly less.Three-dimensional blenders are known and may be obtained from e.g. LavalLab Inc., of the US. The mixing vessel is moved using athree-dimensional motion (known as the Paul Schatz principle) whichcombines a figure-of-eight movement with rotation, causing thesubstances within the mixer to move in a rhythmic, pulsating motion.This motion may mix powders and granulates of differing weights, sizesand flow properties.

The multi-dimension blender utilizes strong physical force in theabsence of a blade to mix materials, rather than a mechanical stirringagitator (as in a planetary dry mixer). This may reduce particle damage(and inconsistent product size) caused by frictional forces between theagitator blade or paddle and mixing vessel side. It also reduces dustfrom particle damage which is believed to affect the homogeneity of thefinal product, and/or sticking onto the mixing vessel internal wall.Further, cleaning is much easier because there is only the smoothinterior surface to clean (no stirring agitator to clean).

The use of the multi-dimension blender or three-dimensional blender isaccompanied by appropriate adjustments to the operational parameters,such as rotation speed, mixing time and material adding frequency.

The new process thus removes or significantly reduces the problemsencountered in the prior process.

The Pre-Mix

In the second stage of the prior process, when producing the pre-mix,the sodium picosulphate was wet mixed with potassium bicarbonate. Duringwet mixing, a part of the potassium bicarbonate was dissolved, and partwas smashed by the stirring agitator; these actions resulted in excessfine powder of potassium bicarbonate in the pre-mix after drying. A lossof product homogeneity was believed to result from this, because overlylarge particles or granules contain less sodium picosulphate, whileoverly fine particles or granules of the dried mixture contain too muchsodium picosulphate; these extremes were believed to affect producthomogeneity. The known process also required that the wet mixture wasdried for a significant period. The known process also required severalmanual steps with the attendant risk of contamination to the product andincreased operator safety concerns.

According to one or more aspects of the present invention, the processincludes a step of applying (e.g. spraying) a solution of sodiumpicosulphate on to the potassium bicarbonate; and drying the sodiumpicosulphate and potassium bicarbonate.

This process for mixing may be thought of as akin to a coating process.The mixing/coating process may be carried out using an automatic tumblecoating machine, e.g. with appropriate adjustments to the operationalparameters made to control the coating level.

Thus, the solution (e.g. aqueous solution) of sodium picosulphate may besprayed onto the potassium bicarbonate; and the said sodium picosulphateand potassium bicarbonate (i.e, the coated pre-mix granules) may bedried in the same equipment. This may lead to a significantly reducedproduction time; for example, the “pre-mix” of sodium picosulphate andpotassium bicarbonate may be produced in about 3 hours [rather thanabout 15 to 24 hours using the prior process].

Further, the applicants found that there may be a significant reductionin inhomogeneity in the product granules, as follows. The sodiumpicosulphate solution may be sprayed very evenly onto the surface of theKHCO₃ granules and dried immediately after applying (e.g. spraying), andthe amount of fine powder may be reduced. The granules are less likelyto be reduced through, for example, smashing of particles/granulesduring a coating-type process. Further, because the coated granules maybe dried instantly or substantially instantly e.g. with warm air, finepowder and dust may be significantly diminished.

Subsequently, the process of the invention may involve mixing ofsaccharin sodium, orange flavour, part of the primary mix and thepre-mix, with subsequent combination with the balance of the primary mix(and mixing) to provide the final homogeneous bulk product.

Thus, the disclosed invention may provide significant improvement inone, two, or more, steps in the mixing process. It may provide a moreefficient process, of improved quality and reproducibility (e.g. withrespect to uniformity of active substance). It may provide a method withreduced risk of contamination and/or loss of material, and/or with lessmanual operation. It may provide a method incurring significantlyreduced process time.

The process according to the present invention may improve thehomogeneity of the intermediate products of the primary mix and pre-mixmixing stages, as well as final product.

The present invention is now described with reference to the followingexamples.

Example 1 Method

Potassium Bicarbonate is sifted on sieves with screen size of 250 μm and600 μm. Purified water is weighed out and Sodium Picosulphate isdissolved in the water to form a sodium picosulphate solution for thePre-Mix stage. Sodium picosulphate solution and potassium bicarbonateare formed into a granulate by using a tumble coater (such coaters arewell known in the art). Potassium Bicarbonate granules are filled intothe coater, and a defined amount of Sodium Picosulphate solution issprayed onto the surface of the granules during operation of the coater.The coated particles are then dried by warm air. After the coatingprocess, pre-mix dried granules of combined Sodium Picosulphate andPotassium Bicarbonate are obtained. FIG. 2 shows SEM pictures and EDAXresults for a premix granule made by this method.Magnesium Oxide and Citric Acid are mixed to form primary mix granulesby using a three-dimensional dry blender. Citric Acid is filled into theblender, and Magnesium Oxide, light is added. The materials in theblender are mixed by the usual operating method. FIG. 1 shows SEMpictures and EDAX results for a prmary mix granule made by this method.Orange flavour and Sodium Saccharin are blended together with Pre-mixand a known quantity of Primary mix to form a flavour blend. The flavourblend is then combined with the balance of Primary mix and mixed. Thecombined Final Blend powder is filled into foil sachets and packagedinto cardboard boxes, using methods known in the art.It is noted that the skilled man would readily understand the amount ofreagent quantities etc to be used (for ex., in a larger scale productionprocess) depending on the amount of product desired.

Example 2 Formulations

The following formulations were made by the method described above. Eachfoil sachet contains the following ingredients.

Example 2b Reagent Example 2a (16.1 g sachet) Example 2c Sodium   9 mg 10 mg   11 mg picosulphate Potassium 0.45 g 0.5 g 0.55 ghydrogencarbonate Magnesium oxide, 3.15 g 3.5 g 3.85 g light Citric acid10.8 g  12 g 13.2 Saccharin sodium   54 mg  60 mg   66 mg Orangeflavour*   54 mg  60 mg   66 mg *natural spray dried orange flavourwhich includes butylated hydroxyanisole

Example 3 SEM Pictures and EDAX Analysis Results

The SEM and EDAX pictures were taken at the Electron Microscope Lab atthe Instrumentation Analysis and Research Centre, Sun Yat-senUniversity, China.FIG. 1 shows SEM picures and EDAX analysis results for a Primary Mixgranule of citric acid and magnesium oxide according to an embodiment ofthe invention, made by the method of Example 1.These pictures show that the element MgO is found on the outer shell ofthe granule. The black and white photo (Electron Image 1) shows aroughly spherical granule, which has been cut on a plane to show thecore of the granule and the shell. The other photo (Mg Ka 1 2) shows thepositon of element Mg (the brighter/whiter dots). Comparing the twophotos, it is evident from the cut away section that the core of thegranule has very little element MgO (the trace amount being due tocontamination during cutting the sample in the preparation process forEDAX), while the shell includes a large quantity of MgO. The SumSpectrum shows the sum of element MgO on the surface of the granule (thecut section and the shell).Further, the black and white photo shows clearly that the granule has acrystal core of Citric Acid and a white shell of MgO. The layerthickness of the MgO shell may be calculated from the black and whitephoto (e.g. using a ruler) to be 5-10 um.FIG. 2 shows SEM picures and EDAX analysis results for a Pre Mix granuleof sodium picosulphate and potassium bicarbonate according to anembodiment of the invention, made by the method of Example 1.The pictures show that the element S (i.e. Sodium Picosulfate) isclearly detected on the shell and the element K (i.e. PotassiumBicarbonate) is clearly detected on the core. The black and white photo(Electron Image 1) shows a Pre-Mix granule which has been cut away toshow the core of the granule and the shell of the granule. The photo SKa 1 shows the position of element S on the granule (dots). It isevident that most element S occupies the shell; the little quantity ofelement S on the cut section plane is contamination caused by thecutting operation in the sample preparation process for EDAX. The photoK Ka 1 shows the position of element K on/in the granule (dots); it canbe seen that the cut section plane (the core of the granule) has more ofelement K than the shell. K Ka 1 and S Ka 1 confirm that the shellincludes both element K and S, indicating that the layer of SodiumPicosulfate is very thin (because its quantity is very low—only 2%according to this formulation of Pre-Mix). The black and white photoshows clearly that the granule has a (crystal) core of Potassiumbicarbonate and a (white) shell of Sodium Picosulfate. The granule maybe described as substantially ellipsoidal.

1. (canceled)
 2. A process for the preparation of a composition whereinsaid process comprises steps of: (a) applying a solution of sodiumpicosulphate on to potassium bicarbonate; and (b) drying the sodiumpicosulphate and potassium bicarbonate.
 3. A process according to claim2 wherein the potassium bicarbonate has a particle diameter betweenabout 100 μm and about 900 μm.
 4. A process according to claim 2 whereinthe potassium bicarbonate is preheated prior to applying the solution ofsodium picosulphate on to the potassium bicarbonate.
 5. A processaccording to claim 2 wherein the sodium picosulphate and potassiumbicarbonate are dried at a temperature of between 30° to 100° C.
 6. Aprocess according to claim 2 wherein the step of drying is performedduring, immediately after or substantially immediately after the step ofapplying.
 7. A process according to claim 2 wherein the steps ofapplying and drying are each applied two or more times, and wherein eachstep of drying is performed during, immediately after or substantiallyimmediately after a step of applying.
 8. A process according to claim 2wherein the composition is in the form of granules or particles.
 9. Aprocess according to claim 8 wherein more than 85% of granules orparticles in the composition have a diameter between about 100 μm andabout 900 μm.
 10. A process according to claim 8 wherein less than 5% ofgranules or particles in the composition have a diameter greater thanabout 900 μm; or wherein less than 5% of granules or particles in thecomposition have a diameter less than about 100 μm.
 11. A processaccording to claim 2 wherein the sodium picosulphate is in aqueoussolution.
 12. (canceled)
 13. A pharmaceutical composition according toclaim 14, wherein the granules have a diameter between about 100 μm andabout 900 μm.
 14. A pharmaceutical composition comprising granulesincluding sodium picosulphate and potassium bicarbonate, the granulescomprising a layer of sodium picosulphate coated on a core of potassiumbicarbonate.
 15. A pharmaceutical composition according to claim 14wherein more than 85% of the granules have a diameter between about 100μm and about 900 μm.
 16. A pharmaceutical composition according to claim14 wherein less than 5% of the granules have a diameter greater thanabout 900 μm; or wherein less than 5% of the granules have a diameterless than about 100 μm.
 17. (canceled)
 18. A process for the preparationof a composition wherein said process comprises a step of dry mixingcitric acid and magnesium oxide to form a homogeneous mixture.
 19. Aprocess according to claim 18 in which the citric acid and magnesiumoxide are dry mixed using a multi-dimension blender or athree-dimensional blender.
 20. A process according to claim 18 in whichthe blender enhances an agglomeration process between citric acid andmagnesium oxide.
 21. A process according to claim 18 in which the citricacid is loaded in a single batch into the blender prior to addition ofmagnesium oxide.
 22. A process according to claim 21 in which themagnesium oxide is added to the single batch of citric acid in batches,with mixing between addition of each batch.
 23. A process according toclaim 18 wherein the citric acid comprises particles having a diameterbetween about 100 μm and about 900 μm.
 24. (canceled)
 25. Apharmaceutical composition comprising granules including citric acid andmagnesium oxide, the granules comprising a layer of magnesium oxidecoated on a core of citric acid.
 26. A pharmaceutical compositionaccording to claim 25 wherein the thickness of the layer of magnesiumoxide is 2 to 15 μm.
 27. (canceled)
 28. A pharmaceutical compositionaccording to claim 25 wherein the granules are between 450 and 800 μmbroad at their broadest point.
 29. A pharmaceutical compositionaccording to claim 25 wherein the granules have a diameter between about100 μm and 900 μm.
 30. A pharmaceutical composition according to claim25 wherein more than 85% of the granules have a diameter between about100 μm and about 900 μm.
 31. A pharmaceutical composition according toclaim 25 wherein less than 5% of the granules have a diameter greaterthan about 900 μm; or wherein less than 5% of the granules have adiameter less than about 100 μm. 32-46. (canceled)
 47. A pharmaceuticalcomposition according to claim 25 wherein the granules comprisemagnesium oxide coated on the citric acid.
 48. A process according toclaim 18 in which the citric acid and magnesium oxide are dry mixedusing a bladeless or paddleless blender.
 49. A process according toclaim 2, which additionally comprises mixing at least a part of thesodium picosulphate and potassium bicarbonate with: (i) a dry mixture ofcitric acid and magnesium oxide, and (ii) optionally, at least one ofsaccharin sodium and orange flavoring.
 50. A process according to claim18, which additionally comprises mixing at least part of the dry mixedcitric acid and magnesium oxide with: (i) a compositiong comprisingsodium picosulphate and potassium bicarbonate, and (ii) optionally, atleast one of saccharin sodium and orange flavoring.